Combinatorial nanomedicine made of squalenoyl-gemcitabine and edelfosine for the treatment of pediatric cancer

Résumé

Chemotherapy protocols for childhood cancers are still problematic due to the high toxicity associated with chemotherapeutic agents, and incorrect dosing regimens extrapolated from adults. Nanotechnology has demonstrated significant ability to reduce toxicity of anticancer compounds. Improvement in the therapeutic index of cytostatic drugs, makes this strategy an alternative to common chemotherapy in adults. Among anticancer nanomedicines, squalenoyl nanocomposites have obtained encouraging outcomes in a great variety of tumors. The prodrug squalenoyl-gemcitabine was chosen in this study to construct a novel multidrug nanosystem in combination with edelfosine, an alkyl-lysophopholipid with proven anticancer activity. Given their amphiphilic nature, it was hypothesized that both anticancer compounds, with complementary molecular targets, could lead to the formation of a new multitherapy nanomedicine. Nanoassemblies were formulated by nanoprecipitation method and characterized by dynamic light scattering, transmission electron microscopy, X-ray photoelectron spectroscopy and UHPLC tandem mass spectroscopy. It was observed that these molecules spontaneously self-assembled as stable and monodisperse nanoassemblies of 51 ± 1 nm in a surfactant/polymer free-aqueous suspension. Compared to squalenoyl-gemcitabine nanoassemblies, the combination of squalenoyl-gemcitabine with edelfosine resulted in smaller particle size and a new supramolecular conformation, with higher stability and drug content. On the other hand, squalenoyl-gemcitabine/edelfosine nanoassemblies were found to be capable of intracellular translocation in patient-derived metastatic pediatric osteosarcoma cells (531M) and showed a better antitumor profile in vitro than squalenoyl-gemcitabine nanoassemblies in neuroblastoma (SH-SY5Y) and pediatric osteosarcoma (U2-OS) cell lines. The intravenous administration of this combinatorial nanomedicine in mice exhibited a controlled release behavior of gemcitabine and diminished edelfosine plasma peak concentrations. For their in vivo pre-clinical assessment in an orthotopic osteosarcoma tumor model, c-Fos overexpressing P1.15 cells were intratibially injected in athymic nude mice. In comparison with the control groups, the combinatorial nanomedicine was found to decrease the primary tumor growth kinetics and to reduce the number of lung metastases. Our findings support the candidature of squalenoyl-gemcitabine/edelfosine nanoassemblies as a potential pediatric cancer therapy. Improving the quality of life of cancer patients is essential, particularly in the case of the pediatric population. In these studies, we successfully designed squalenoyl-gemcitabine/edelfosine nanoassemblies of 50 nm, which proved to be safe and efficacious in a murine osteosarcoma model. The findings gathered in this thesis shed light on the promising future of combinatory nanomedicine to replace current cancer treatments.